Biology subjects

Cremer, S.

Publications and source records attributed to Cremer, S..

14 recordsLinked to original sources

bioRxiv2026

Viral infection patterns in ants are affected by colony structure and phylogenetic lineage

Across ant species, there are differences in how their societies are structured. Single-queened (monogynous) societies only have one reproducing queen in the colony, and new queens disperse and start colonies independently. In multiple-queened (polygynous) societies, the colony instead can contain several reproductive queens, and newborn queens often remain and reproduce within their natal colony. As a result, polygynous societies are comparatively larger, more genetically diverse, and can span large areas through several interconnected nests, whereas monogynous societies are typically smaller in scale. In this study, we investigated how these different social structures, as well as their phylogenetic lineage, affect the diversity (number of virus species per ant sample) and abundance (number of viral sequences per sample) of viruses in ants. We produced pooled RNA sequence libraries from 15 ant species, representing both monogynous and polygynous social structures, and the two largest ant subfamilies: Formicinae and Myrmicinae, with each library containing the RNA of up to 400 individual worker ants from a single population. We identified 168 virus species in total, of which 152 species were new to science. Out of these 168 viruses, 59 were active viruses based on the host immune response. We observed that polygynous ant species harbor a higher diversity of viruses and also tend to have higher virus abundance compared to monogynous species. Also, the ant subfamily Myrmicinae had a higher virus diversity than Formicinae. These findings highlight how social structure and evolutionary history shape viral diversity in ants.

genomics↗

bioRxiv2025

Haematopoietic loss of KDM6A impairs cardiac recovery in heartfailure via epigenetic reprogramming of myeloid cells

Clonal haematopoiesis (CH) is recognized as a potent independent risk factor for cardiovascular disease (CVD). While mutations in common CH-associated genes, such as DNMT3A and TET2, have been extensively studied, the pathological roles of other CH mutations remain poorly understood. Among these is KDM6A (UTX), an X-linked histone demethylase recently found to be commonly mutated in patients with heart failure. The mechanistic implications of KDM6A mutations in cardiac dysfunction remain largely unknown. Here, using multi-omics profiling and functional characterisation of murine models and patient-derived data, we demonstrate that haematopoietic loss of KDM6A substantially impairs cardiac recovery following myocardial infarction (MI). KDM6A deficiency enhances systemic and cardiac inflammation, characterized by augmented myeloid cell infiltration into the infarcted murine heart. Single-cell chromatin accessibility and single-cell RNA sequencing analyses revealed profound epigenetic and transcriptional reprogramming in KDM6A-deficient myeloid cells, notably CCR2 recruited macrophages and neutrophils. These cells exhibited heightened inflammatory (Il1b, Nlpr3, Saa3) and chemotactic signatures (Ccr2, Mif, Cxcl12), increased activation of inflammatory transcription factor networks (AP-1, C/EBP), disrupted chromatin architecture, and enhanced glycolytic activity. Clinically, patients with heart failure harbouring KDM6A-driven CH exhibited increased pro-inflammatory monocyte signatures (CCR2, NLPR3, NFKB1, FOS, JUN, IL6R, IL32), underscoring the translational relevance. Integrative analyses further predicted pathogenic crosstalk between KDM6A-mutated monocytes and cardiac resident cells and was experimentally validated by demonstrating that KDM6A-silenced macrophages drive cardiomyocyte hypertrophy and cardiac fibroblast activation. Our findings establish a critical mechanistic link between KDM6A-driven CH, immune dysregulation, and worsened cardiac outcomes post-MI, highlighting novel avenues for personalized therapeutic strategies in heart failure.

cell biology↗

bioRxiv2025

ALTAA: analysis of long-term activity patterns in ant colonies

Collective behaviours are a fascinating study area due to the emergent properties that can only arise in groups of interacting individuals. However, their quantitative study is often impaired by technical difficulties, creating either low-quality and sparse data, or impractical data amounts, particularly when capturing large groups over long periods of time. Common challenges arise from recording group members with as little obscuring of each other as possible, as well as in generating manageable data amounts with as high as possible information content. We here provide a multi-component system that allows to record, analyze and simulate the long-term spatiotemporal activity patterns of insect collectives, especially ant colonies. Our Ant Observing System, ALTAA, comprises a flat nest design to prevent occlusion of individuals, a recording system running on a low-power single-board-computer, and a set of computer programs performing quantitative analyses to guide the formation and validation of rules underlying the observed collective patterns. Our system is scalable in that it allows parallel, continuous observation of a high number of colonies using low memory space, with colony maintenance requirements (e.g. feeding, nest humidity) being achieved at lowest possible disturbance by the experimenter. We showcase the potential of the system in a study using the black garden ant, Lasius niger, where we analyze the spatiotemporal effects of different group size (1, 6, 10 ants), brood (larvae) presence or absence, as well as of different nest geometries, over a period of one week. We show that the ants motion activity has a weak periodicity in the range of 20 to 120 minutes promoted by larval presence, and that ants are spatially attracted to their larvae, the water source and the walls. We also find that the presence of nestmates lowers an individual ants motion activity. Observed data are compared to simulations of the temporal activity of the ants. ALTAA provides a powerful toolkit to quantify and interpret spatial and temporal collective activity patterns in (social) insects over extended periods.

animal behavior and cognition↗

bioRxiv2024

Metabolic alterations drive inflammatory phenotypes in CHIP-associated heart failure

Mutations in DNA methyltransferase 3 alpha (DNMT3A) are the most frequent driver of clonal hematopoiesis of indeterminate potential (CHIP), and associated with higher risk of cardiovascular disease and pro-inflammatory activation of immune cells. Here, we investigated the mechanisms underlying DNMT3A CHIP-associated inflammatory phenotypes in macrophages. We show that monocytes of DNMT3A CHIP-driver mutation carriers are associated with DNA hypomethylation of succinate dehydrogenase A (SDHA) and an altered tricarboxylic acid cycle metabolite profile. Silencing of DNMT3A in monocytes increased SDHA and elevated mitochondria complex II activity. The secreted complex II product, malate, further increased inflammatory activation in wild type monocytes to further augment inflammation in a paracrine manner. Pharmacological inhibition of SDHA (using dimethyl malonate) in mice harboring DNMT3A mutations in hematopoietic stem cells ameliorated the inflammatory response and improved cardiac function after myocardial infarction. Thus, interfering with the altered metabolic state may provide a new therapeutic option to dampen inflammatory activation in DNMT3A CHIP carrying patients.

molecular biology↗

bioRxiv2024

Inhibiting monocyte migration reduces arterial thrombosis and facilitates thrombolysis

BackgroundMonocytes contribute to the initiation and propagation of venous thrombosis. Little is known about the roles monocytes play in arterial thrombosis, the cause of stroke and MI. MethodsWe investigated how chemokine receptor 2 (CCR2) knockout (-/-) affects platelet function, blood coagulation, thrombus volume, and thrombolytic susceptibility in 627 mice with FeCl3-mediated carotid arterial thrombosis: three CX3CR1-GFP mice, 326 C57BL/6 mice, and 288 CCR2-/- mice. We performed i) intravital microscopy imaging of leukocyte recruitment to carotid thrombus, ii) flow cytometry-based quantification of leukocytes in blood vs. thrombus and leukocyte-platelet aggregates in blood, iii) platelet aggregometry, iv) coagulation assays, v) micro-computed tomography (microCT)-based thrombus imaging using gold nanoparticles after tissue plasminogen activator (tPA) therapy with or without either a) CCR2 siRNA pretreatment (for 3 days) or post-treatment or b) clopidogrel pretreatment (for 7 days), and vi) histology including scanning electron microscopy. ResultsIntravital microscopy and flow cytometry showed that both neutrophils and monocytes were recruited to the acute arterial thrombus, as observed 30 minutes post-thrombosis. Platelet function tests demonstrated platelet aggregation to be lower in the whole blood of CCR2-/- mice (vs. C57BL/6 mice) but not in their leukocyte-free platelet rich plasma, suggesting this platelet dysfunction is cell-mediated. Flow cytometry experiments revealed lower numbers of monocyte - platelet aggregates (MPAs), a marker of platelet activity, in the blood of CCR2-/- mice, compared to C57BL/6 mice. Blood levels of FXIII and monocyte levels of FXIII-A were increased after carotid thrombosis in C57BL/6 mice but not CCR2-/- mice. Further, in vivo microCT and histology, respectively, showed that CCR2-/- mice had smaller and more porous thrombi with less fibrin cross-linking, compared with C57BL/6 mice. MicroCT also demonstrated that tPA-mediated thrombolysis was faster in CCR2-/- mice and CCR2 siRNA-treated mice, compared to C57BL/6 mice. In addition, clopidogrel had a greater effect on inducing thrombus formation with smaller sizes after FeCl3 application, while CCR2-/- had a greater effect on dissolving thrombus faster after tPA administration. ConclusionsCCR2 antagonism decreases platelet aggregation and reduces FXIII levels in blood and monocytes, thus driving arterial thrombosis towards the generation of a relatively small, porous, more lysable clot. Novelty and SignificanceO_ST_ABSWhat Is Known?C_ST_ABSO_LIIn venous thrombosis, monocytes cooperate with platelets and neutrophils to promote thrombus formation; however, few studies have investigated the roles of monocytes in arterial thrombosis. C_LIO_LIAn in vitro study using arterial blood samples from patients with acute coronary syndrome showed that P-selectin on activated platelets upregulated monocyte chemokine receptor 2 (CCR2) expression, which was higher in monocyte-platelet aggregates (MPAs) than in monocytes without platelets. C_LIO_LIIn a mouse study using an in vivo model of FeCl3-induced arterial thrombosis, the time to thrombotic occlusion was prolonged in CC chemokine ligand 2 (CCL2) knockout (-/-) mice compared with wild-type mice. C_LI What New Information Does This Article Contribute?O_LIThis study is the first to demonstrate that CCR2-/--mediated monocyte deficiency exerts antithrombotic and tissue plasminogen activator (tPA)-facilitating effects in acute arterial thrombosis. C_LIO_LICCR2-/- mice had a) decreased platelet aggregability, probably due in part to reduced post-thrombosis MPA numbers, and b) lower blood and monocyte levels of Factor XIII (FXIII), compared to those of C57BL/6 mice. C_LIO_LIMicro-computed tomography (microCT) thrombus imaging showed that i) CCR2-/- mice, compared to C57BL/6 mice, had smaller thrombi, with more porosity and less fibrin cross-linking on histology and ii) CCR2-/- or CCR2 siRNA facilitates tPA-mediated thrombolysis. C_LI The majority of ischemic strokes occur due to thromboembolic occlusion of cerebral arteries. Tissue plasminogen activator (tPA), which is the only FDA-approved drug for acute ischemic stroke, has only a moderate efficacy rate regarding early recanalization, which is closely associated with thrombus volume and thrombolytic resistance. Monocytes, in cooperation with platelets and neutrophils, contribute to thrombus formation in venous thrombosis. To date, only a few studies have detailed potential prothrombotic roles for monocytes in arterial thrombosis. In the present study, using a mouse model of FeCl3-mediated carotid artery thrombosis and high-resolution microCT thrombus imaging, we demonstrate that CCR2-/--mediated monocyte deficiency exerts antithrombotic and tPA-facilitating effects. Compared to C57BL/6 mice, CCR2-/- mice exhibited decreased platelet aggregability along with lower numbers of circulating MPAs (a marker of platelet activity) and reduced monocyte recruitment to arterial thrombi. Moreover, CCR2-/- mice had lower levels of both circulating FXIII and monocyte FXIII-A, which are known to strengthen and stabilize thrombi. In line with these findings, i) CCR2-/- mice had smaller, more porous thrombi with less fibrin cross-linking and ii) tPA-mediated thrombolysis was faster in CCR2-/- mice or with CCR2 siRNA.

immunology↗

bioRxiv2024

Altruistic disease signalling in ant colonies

Sick individuals often conceal their disease status to group members, thereby preventing social exclusion or aggression. Here, we show that infected ant pupae, on the contrary, actively emit a chemical signal that triggers their own destruction by colony members. In our experiments, this altruistic disease-signalling was performed only by worker but not queen pupae, reflecting differences in their immune capabilities, as worker pupae suffered from extensive pathogen replication whereas queen pupae were able to restrain infection. Inducing others to sacrifice oneself, only if ones own immunity fails, suggests a fine-tuned interplay between individual and social immunity, efficiently achieving whole-colony health.

animal behavior and cognition↗

bioRxiv2023

Fungal infection alters collective nutritional intake of ant colonies

In many animals, parasitic infections impose significant fitness costs [1-6]. Animals are known to alter their feeding behavior when infected to help combat various parasites [7-12]. For instance, they can adjust nutrient intake to support their immune system [13,14]. However, parasites can also manipulate host foraging behavior to increase their own development, survival and transmission [15-18]. The mechanisms by which nutrition influences host-parasite interactions are still not well understood. Until now, studies that examine the impact of diet on infection have mainly focused on the host, and less on the parasite [12,13, 19-25]. Using Nutritional Geometry [26], we investigated the role of key nutrients: amino acids and carbohydrates, in a host-parasite system: the Argentine ant, Linepithema humile, and the entomopathogenic fungus, Metarhizium brunneum. We first established that the fungus grew and reproduced better on diets comprising four times less amino acids than carbohydrates (1:4 AA:C ratio). Second, when facing food combinations, the fungus exploited the two complementary food resources to reach the same performance as on this optimal diet, revealing the ability of fungal pathogens to solve complex nutritional challenges. Third, when ants were fed on this optimal fungal diet, their lifespan decreased when healthy, yet not when Metarhizium-infected, compared to their favored carbohydrate-rich diet. Interestingly, when the ants were given a binary choice between different diets, the foragers of uninfected colonies avoided intake of the fungal optimum diet, whilst choosing it when infected. Experimental disentanglement of full pathogenic infection and pure immune response to fungal cell wall material, combined with immune measurements, allowed us to conclude that this change of nutritional choice in infected ants did not result from pathogen manipulation but likely represents a compensation of the host to counterbalance the cost of using amino acids during the immune response. The observed change in foraging behavior in infected colonies towards an otherwise harmful diet (self-medication), suggests a collective compensatory mechanism for the individual cost of immunity. In short, we demonstrated that infected ants converge on a diet that is proven to be costly for survival in the long term but that could help them fight infection in the short term. HighlightsO_LIThe insect-pathogenic fungus Metarhizium brunneum performs best on protein-rich diets and is able to solve complex nutritional challenges C_LIO_LIWhile harmful to healthy ants, protein-rich diets did not shorten infected ants lifespan C_LIO_LIContrary to healthy ants, when given a choice, infected and immune-stimulated ants choose a protein-rich diet C_LI

animal behavior and cognition↗

bioRxiv2023

Frequent horizontal chromosome transfer between asexual fungal insect pathogens

Entire chromosomes are typically only transmitted vertically from one generation to the next. The horizontal transfer of such chromosomes has long been considered improbable, yet gained recent support in several pathogenic fungi where it may affect the fitness or host specificity. To date, it is unknown how these transfers occur, how common they are and whether they can occur between different species. In this study, we show multiple independent instances of horizontal transfers of the same accessory chromosome between two distinct strains of the asexual entomopathogenic fungus Metarhizium robertsii during experimental co-infection of its insect host, the Argentine ant. Notably, only the one chromosome - but no other - was transferred from the donor to the recipient strain. The recipient strain, now harboring the accessory chromosome, exhibited a competitive advantage under certain host conditions. By phylogenetic analysis we further demonstrate that the same accessory chromosome was horizontally transferred in a natural environment between M. robertsii and another congeneric insect pathogen, M. guizhouense. Hence horizontal chromosome transfer is not limited to the observed frequent events within species during experimental infections but also occurs naturally across species. The transferred accessory chromosome contains genes that might be involved in its preferential horizontal transfer, encoding putative histones and histone-modifying enzymes, but also putative virulence factors that may support its establishment. Our study reveals that both intra- and interspecies horizontal transfer of entire chromosomes is more frequent than previously assumed, likely representing a not uncommon mechanism for gene exchange. Significance StatementThe enormous success of bacterial pathogens has been attributed to their ability to exchange genetic material between one another. Similarly, in eukaryotes, horizontal transfer of genetic material allowed the spread of virulence factors across species. The horizontal transfer of whole chromosomes could be an important pathway for such exchange of genetic material, but little is known about the origin of transferable chromosomes and how frequently they are exchanged. Here, we show that the transfer of accessory chromosomes - chromosomes that are non-essential but may provide fitness benefits - is common during fungal co-infections and is even possible between distant pathogenic species, highlighting the importance of horizontal gene transfer via chromosome transfer also for the evolution and function of eukaryotic pathogens.

genomics↗

bioRxiv2023

Trade-offs between immunity and competitive ability in fighting ant males

BackgroundFighting disease while fighting rivals exposes males to constraints and tradeoffs during male-male competition. We here tested how both the stage and intensity of infection with the fungal pathogen Metarhizium robertsii interfered with fighting success in Cardiocondyla obscurior ant males. Males of this species have evolved long lifespans during which they can gain many matings with the young queens of the colony, if successful in male-male competition. Since male fights occur inside the colony, the outcome of male-male competition can further be biased by interference of the colonys worker force. ResultsWe found that severe, but not yet mild, infection strongly impaired male fighting success. In late-stage infection, this could be attributed to worker aggression directed towards the infected rather than the healthy male and an already very high male morbidity even in the absence of fighting. Shortly after pathogen exposure, however, male mortality was particularly increased during combat. Since these males mounted a strong immune response, their reduced fighting success suggests a trade-off between immune investment and competitive ability already early in the infection. Even if the males themselves showed no difference in the number of attacks they raised against their healthy rivals across infection stages and levels, severely infected males were thus losing in male-male competition from an early stage of infection on. ConclusionsMales of the ant C. obscurior have evolved high immune investment, triggering an effective immune response very fast after fungal exposure. This allows them to cope with mild pathogen exposures without cost to their success in male-male competition, and hence to gain multiple mating opportunities with the emerging virgin queens of the colony. Under severe infection, however, they are weak fighters and rarely survive a combat already at early infection when raising an immune response, as well as at progressed infection, when they are morbid and preferentially targeted by worker aggression. Workers thereby remove males that pose a future disease threat by biasing male-male competition. Our study thus revealed a novel social immunity mechanism how social insect workers protect the colony against disease risk.

evolutionary biology↗

bioRxiv2023

DNMT3A clonal hematopoiesis-driver mutations induce cardiac fibrosis by paracrine activation of fibroblasts

Hematopoietic mutations in epigenetic regulators like DNA methyltransferase 3 alpha (DNMT3A) drive clonal hematopoiesis of indeterminate potential (CHIP) and are associated with adverse prognosis in patients with heart failure (HF). The interactions between CHIP-mutated cells and other cardiac cell types remain unknown. Here, we identify fibroblasts as potential interaction partners of CHIP-mutated monocytes using combined transcriptomic data from peripheral blood mononuclear cells of HF patients with and without CHIP and the cardiac tissue. We demonstrate that CHIP augments macrophage-to-cardiac fibroblasts interactions. Mechanistically, the secretome of DNMT3A-silenced monocytes leads to myofibroblast activation, partially through epidermal growth factor (EGFR) signaling. Harboring DNMT3A CHIP-driver mutations is associated with increased cardiac interstitial fibrosis in mice and patients, and, thereby, may contribute to the poor outcome. These findings not only identify a novel pathway of DNMT3A CHIP-driver mutation-induced instigation and progression of HF, but may also provide a rationale for the development of new anti-fibrotic strategies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/521766v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@10a365aorg.highwire.dtl.DTLVardef@176807borg.highwire.dtl.DTLVardef@ed3f47org.highwire.dtl.DTLVardef@1d572b2_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2022

Antiviral immune response reveals host-specific virus infections in natural ant populations

Hosts can carry many viruses in their bodies, but not all of them cause disease. We studied ants as a social host to determine both their overall viral repertoire and the subset of actively infecting viruses across natural populations of three subfamilies: the Argentine ant (Linepithema humile, Dolichoderinae), the invasive garden ant (Lasius neglectus, Formicinae) and the red ant (Myrmica rubra, Myrmicinae). We used a dual sequencing strategy to reconstruct complete virus genomes by RNA-seq and to simultaneously determine the small interfering RNAs (siRNAs) by small RNA sequencing (sRNA-seq), which constitute the host antiviral RNAi immune response. This approach led to the discovery of 41 novel viruses in ants and revealed a host-ant specific RNAi response (21 vs. 22 nt siRNAs) in the different ant species. The efficiency of the RNAi response (sRNA/RNA read count ratio) depended on the virus and the respective ant species, but not its population. Overall, we found the highest virus abundance and diversity per population in Li. humile, followed by La. neglectus and M. rubra. Argentine ants also shared a high proportion of viruses between populations, whilst overlap was nearly absent in M. rubra. Only a single of the total 59 viruses in our study caused active infection in more than one ant species, whilst six viruses infected one, but only contaminated another ant species. Disentangling active infection from contamination thus allowed us to show high host-specificity of active viral infections versus a decent degree of spillover of non-infecting viral contaminants across ant species, providing relevant information for ecosystem management.

microbiology↗

bioRxiv2019

A mouse model of recurrent myocardial infarction reports diminished emergency hematopoiesis and cardiac inflammation

Recurrent MI is common in patients with coronary artery disease and associates with high mortality. Here we developed a surgical mouse model in which two subsequent MIs affect different left ventricular regions in the same mouse. Recurrent MI was induced by ligating the left circumflex followed by the left anterior descending branch of the coronary artery. We characterized the resulting ischemia by whole-heart fluorescent coronary angiography after optical organ clearing and by cardiac MRI. We report that a first MI induces bone marrow \"memory\" via a circulating signal, thereby affecting hematopoietic factor expression in bone marrow macrophages. This altered the organisms reaction to subsequent events. Inspite at least similar extent of injury reported by blood troponin, recurrent MI caused reduced emergency hematopoiesis and less leukocytosis than a first MI. Consequently, fewer leukocytes migrated to the ischemic myocardium. The hematopoietic response to lipopolysaccharide was also mitigated after a previous MI. Our data suggest that hematopoietic and innate immune responses are shaped by a preceding MI.

physiology↗

bioRxiv2017

Ants express risk-adjusted sanitary care

Being cared for when sick is a benefit of sociality that can reduce disease and improve survival of group members. However, individuals providing care risk contracting infectious diseases themselves. If they contract a low pathogen dose, they may develop micro-infections that do not cause disease, but still affect host immunity by either decreasing or increasing the hosts vulnerability to subsequent pathogen infections. Caring for contagious individuals can thus significantly alter the future disease susceptibility of caregivers. Using ants and their fungal pathogens as a model system, we here tested if the altered disease susceptibility of experienced caregivers, in turn, affects their expression of sanitary care behaviour. We found that micro-infections contracted during sanitary care had protective or neutral effects upon secondary exposure to the same (homologous) pathogen, but consistently induced high mortality upon super-infection with a different (heterologous) pathogen. In response to this risk, the ants selectively adjusted the expression of their sanitary care. Specifically, the ants performed less grooming yet more antimicrobial disinfection, when caring for nestmates contaminated with heterologous pathogens as compared to homologous ones. By modulating the components of sanitary care in this way, the ants reduced their probability of contracting super-infections of the harmful heterologous pathogens. The performance of risk-adjusted sanitary care reveals the remarkable capacity of ants to react to changes in their disease susceptibility, according to their own infection history, and to flexibly adjust collective care to individual risk.

evolutionary biology↗

bioRxiv2017

Destructive Disinfection Of Infected Brood Prevents Systemic Disease Spread In Ant Colonies

Social insects protect their colonies from infectious disease through collective defences that result in social immunity. In ants, workers first try to prevent infection of colony members. Here, we show that if this fails and a pathogen establishes an infection, ants employ an efficient multicomponent behaviour - \"destructive disinfection\" - to prevent further spread of disease through the colony. Ants specifically target infected pupae during the pathogens non-contagious incubation period, relying on chemical sickness cues emitted by pupae. They then remove the pupal cocoon, perforate its cuticle and administer antimicrobial poison, which enters the body and prevents pathogen replication from the inside out. Like the immune system of a body that specifically targets and eliminates infected cells, this social immunity measure sacrifices infected brood to stop the pathogen completing its lifecycle, thus protecting the rest of the colony. Hence, the same principles of disease defence apply at different levels of biological organisation.

evolutionary biology↗